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14 Detection of cystic fibrosis mutations in echogenic bowel
Journal of Cystic Fibrosis 4 (2005) $ 3 ~ 1 0
$7
13 Genotype-phenotype relationship study in a large cohort of 1717-1G-->A/DeltaFS08 CF patients.
15 CFTR mutations and polymorphisms in patients with disseminated
I. D u g u ~ l ~ r oux, M. D e Braekeleer
A. Divac 1, A. Nikolic 1, M. Mitic MilikJc2, Lj. Nagorni Obr adovic ~, N. Petr ovic St anojevicz, V. Dopudj a Fantic z, D. Radoj kovic 1
FacuItd de Mddecine & CHU Morva~ Brest, France We report here data from the French CF registry on 67 CF patients bearing the 1717 1G >A/DeltaF508 genotype. Each compound heter ozygote was matched to a AF508 homozygote of same sex, age (+ 1 year) and attending the same CF care network. Both populations w e r e 13 years old at the t i m e of the study, 7 6 % of the patients being younger than 20 years. T h e m e a n age at diagnosis was similar in both groups: 18.5 months + 31.7 versus 20.1 + 33.2 respectively. No difference was found in the clinical clues at the t i m e of diagnosis, except for a higher frequency of meconium ileus among the 1717 1G >A/AF508 patients (24.2% versus 10.9% P 0.04). Both groups had poor nutritional status and a m e a n B M I under normal values (16.7 versus 16.8 kg/m~). T h e m e a n F E V 1 scores w e r e below 75%. The m e a n F V C score was lower, but not significantly, in the 1717 1G >A/AF508 group than among the AF508 homozygotes (77.7 + 23.4 versus 86.8 + 22.9 % of predicted value; p 0.07). However, the median values w e r e closer: 83.3 % versus 85.8%. T h e m e a n sweat chloride concentration and the prevalence of clinical events, s~ach as liver cirrhosis and mellitus diabetes, w e r e similar in both groups. Almost all patients w e r e pancreatic insnfficient. In conclusion, the 1717 1 G > A allele leads to a severe phenotype indistinguishable from the AF508 mutation, but for an increased risk of meconium ileus. The authors t h a n k the participating centres and the I N E D t e a m ha charge of the m a n a g e m e n t of the French CF Registry. Ingrid D u g u g l ~ r o u x is the recipient of a post
14" Detection of Cystic Fibrosis mutations in echogenic bowel M Tzetis, A Tsiamouri, A Papatheodor ou, K Pouliou, E Keaaavakis
Dept of Medical Genetics, University of Athens, St. Sophia's ChiMren's Hospital, Athens, Greece The presence of echogenic bowel detected on ultrasound investigation during the second trimester of preDaancy can be a normal variant and also associated with cystic fibrosis, as w e l l as a number of other disorders such as cbromosome aneuploidy. W e h a v e investigated 91 cases of echogenic bowel and h a v e detected cystic fibrosis homozygosity in four of these (4.3%) w i t h the following genotypes: F508del/L732X, F508del/574delA, F508del/F508del, F508del/G542X. In addition heterozygosity was observed in 15 cases (13.4%): 9 w i t h F508del 2 w i t h 621 + I G > T and 1 case each for I148T, 2789+5G>A, R 2 9 7 Q and E822X. A n additional finding was the presence of particular polymotpbisms: 3 instances of 1716G/A (E528E), 2 of 2 7 5 2 15G/C, 2 of R l 1 6 2 L and 1 of 4029A/G. Our data indicated that the prior risk of CF in a fetus w i t h echogenic bowel for our population is 4.3% and the r e m a i n i n g risk of an heterozygous fetus having CF is between 10.3 and 20%. Table 1: Summary of familieztezted and CF rezultz Both parents and/or fetus negative One parent cartier fetus negative One parent cartier fetus not tested
21 2 5
One parent cartier fetus cartier
7
Both parents carriers fetus affected
4
Fetuz only tezted negative Fetuz only tezted cartier
18 8
Coup~ o n ~ z t e d TOTAL
26 91
both negative
I148T, F308del 69 I+3A>G, R75Q and 3 with F308del, 69 I+IG>T, I148T and 5 with F308del F308del/L73?X, F308del/374delA, F308del/F308del, F308del/G542X E822X; ?789+3G>A; 67 I+IG>T; R297Q; and 4 F308del 4 homozygotez and 15 heterozygotez
bronchiectasis IlMGGE, Serbia & Montenegro, 21nstitute for tuberculosis a~u] lung disease, University Clinical Center of Serbia, Belgrade, Serbia & Montenegro, SUniversity Clinical Center Zvezdara, Department of PuImonology, Belgrade, Serbia &Montenegro W e tested the possible involvement of C F I R mutations and polymotphisms in etiology of disseminated bronchiectasis ( D E ) of u n k n o w n cause, in 19 Serbian patients T h e w h o l e coding region and intr onic boundaries of the CFFR g e n e w e r e analyzed by d e n a t u r i n g gradient g e l electropboresis ( D G G E ) mad subsequent D N A sequencing. In 2/19 patients, two different CFTR mutations w e r e detected. One patient was a compound heterozygote (V920L/R75Q) and one was heterozygous for R75Q. T h e cumulative allelic frequency of mutations was 7.9% (3/38 alleles). IVS8 5T allele was not found ha any of the patients. T h e incidence of the M 4 7 0 allele was 28.9% (11/38 alleles). Several common silent mutations (1716G/A, 2694T/G, 4002A/C~ 4404C/T) and nucleotide changes ha n o n coding regions (875+40A/G, GATT6/7, 1011+11C/T) w e r e identified. Frequency of CFTR mutations obtained ha this study was not significantly higher than in general population and our results do not indicate a maj or role of CFFR g e n e mutations ha the etiology of D B . In spite of the facts that the clinical selection of patients was strict mad that the complete coding region of the CFTR g e n e was screened, d u e to the small sample size, these results should be considered preliminary and need to be confirmed in a larger study. Recent publications by K i n g et al and Casals et al reported controversial results regarding the involvement of CFFR ha development of D B , so further multicentre studies on a larger cobott of clinically w e l l defined patients are needed to resolve these conflicting results.
16 Influence of Interleukin-1O on airways colonizafion by Aspergillus fumigatusin cystic fibrosis patients J. Brouard 1'2, N. ICmaner 1'3, P.Y. Boelle4, H. Corvol 1'5, A. Henrion Caude 1, C. Flamant 1, F. Bremont ~, B. Delaisi7, J.F. D u h a m e l ~, C. M a r guet 8, M. Roussey 9, M.C. Miesch 1, K. Chadelat 1'5, M. B o u l e 1'5, B. Faur oux 1'5, F. Ratjen3, H. Gr asemann 3, A. Clement 1,5
llnserm U719, Armand Trousseau Hospital, Paris, France; ~Departrnent of Paediatrics, Georges Cldme~weau Hospital, Cae~ Fra~we; sChildren's Hospital, University of Essetg Essetg Germany; 4Departrnent of B iostatistic, Inserm U444, StAntoine Hospital, Paris, Fratwe; ~Department of Paediatric Pneumology, Armand Trousseau Hospital, Paris, France; 6Department of Pneumology and GastroenterologN Purpan Children's Hospital, Toulouse, Fratwe; 7Department of Paediatrics, Robert Debrd ChiMren's Hospital, PaAs, France; aDepartment of Paediatrics, Charles NicoIle Hospital, Rouen, Fratwe; ;Department of Paediatrics, South Hospital, Rennes, Fratwe Recent evidence suggests that genetic variants affecting t h e production of interleukin (IL) 10 may play a role in the response to pathogens ha cystic fibrosis (CF). T h e study was designed to seek for an association between alleles carried at position 1 0 8 2 o f t h e l L 10promoter and phenotypical data from 378 patients w i t h CF. After adjusting for potential confounding variables a significant relationship was found between the 1082GGgenotypeandbothAfumigatuscolonizationand allergic bronchopulmonary aspergillosis (ABPA). In addition, higher serum levels of I L 10 w e r e observed ha patients chronically infected w i t h Afurnigatus, and this was associated w i t h a significant increased frequency of 1082G allele. These genetic and functional studies suggest that promoter variants of I L 10 may predispose to develop A fumigatus colonization and A B P A ha CF.
$7
13 Genotype-phenotype relationship study in a large cohort of 1717-1G-->A/DeltaFS08 CF patients.
15 CFTR mutations and polymorphisms in patients with disseminated
I. D u g u ~ l ~ r oux, M. D e Braekeleer
A. Divac 1, A. Nikolic 1, M. Mitic MilikJc2, Lj. Nagorni Obr adovic ~, N. Petr ovic St anojevicz, V. Dopudj a Fantic z, D. Radoj kovic 1
FacuItd de Mddecine & CHU Morva~ Brest, France We report here data from the French CF registry on 67 CF patients bearing the 1717 1G >A/DeltaF508 genotype. Each compound heter ozygote was matched to a AF508 homozygote of same sex, age (+ 1 year) and attending the same CF care network. Both populations w e r e 13 years old at the t i m e of the study, 7 6 % of the patients being younger than 20 years. T h e m e a n age at diagnosis was similar in both groups: 18.5 months + 31.7 versus 20.1 + 33.2 respectively. No difference was found in the clinical clues at the t i m e of diagnosis, except for a higher frequency of meconium ileus among the 1717 1G >A/AF508 patients (24.2% versus 10.9% P 0.04). Both groups had poor nutritional status and a m e a n B M I under normal values (16.7 versus 16.8 kg/m~). T h e m e a n F E V 1 scores w e r e below 75%. The m e a n F V C score was lower, but not significantly, in the 1717 1G >A/AF508 group than among the AF508 homozygotes (77.7 + 23.4 versus 86.8 + 22.9 % of predicted value; p 0.07). However, the median values w e r e closer: 83.3 % versus 85.8%. T h e m e a n sweat chloride concentration and the prevalence of clinical events, s~ach as liver cirrhosis and mellitus diabetes, w e r e similar in both groups. Almost all patients w e r e pancreatic insnfficient. In conclusion, the 1717 1 G > A allele leads to a severe phenotype indistinguishable from the AF508 mutation, but for an increased risk of meconium ileus. The authors t h a n k the participating centres and the I N E D t e a m ha charge of the m a n a g e m e n t of the French CF Registry. Ingrid D u g u g l ~ r o u x is the recipient of a post
14" Detection of Cystic Fibrosis mutations in echogenic bowel M Tzetis, A Tsiamouri, A Papatheodor ou, K Pouliou, E Keaaavakis
Dept of Medical Genetics, University of Athens, St. Sophia's ChiMren's Hospital, Athens, Greece The presence of echogenic bowel detected on ultrasound investigation during the second trimester of preDaancy can be a normal variant and also associated with cystic fibrosis, as w e l l as a number of other disorders such as cbromosome aneuploidy. W e h a v e investigated 91 cases of echogenic bowel and h a v e detected cystic fibrosis homozygosity in four of these (4.3%) w i t h the following genotypes: F508del/L732X, F508del/574delA, F508del/F508del, F508del/G542X. In addition heterozygosity was observed in 15 cases (13.4%): 9 w i t h F508del 2 w i t h 621 + I G > T and 1 case each for I148T, 2789+5G>A, R 2 9 7 Q and E822X. A n additional finding was the presence of particular polymotpbisms: 3 instances of 1716G/A (E528E), 2 of 2 7 5 2 15G/C, 2 of R l 1 6 2 L and 1 of 4029A/G. Our data indicated that the prior risk of CF in a fetus w i t h echogenic bowel for our population is 4.3% and the r e m a i n i n g risk of an heterozygous fetus having CF is between 10.3 and 20%. Table 1: Summary of familieztezted and CF rezultz Both parents and/or fetus negative One parent cartier fetus negative One parent cartier fetus not tested
21 2 5
One parent cartier fetus cartier
7
Both parents carriers fetus affected
4
Fetuz only tezted negative Fetuz only tezted cartier
18 8
Coup~ o n ~ z t e d TOTAL
26 91
both negative
I148T, F308del 69 I+3A>G, R75Q and 3 with F308del, 69 I+IG>T, I148T and 5 with F308del F308del/L73?X, F308del/374delA, F308del/F308del, F308del/G542X E822X; ?789+3G>A; 67 I+IG>T; R297Q; and 4 F308del 4 homozygotez and 15 heterozygotez
bronchiectasis IlMGGE, Serbia & Montenegro, 21nstitute for tuberculosis a~u] lung disease, University Clinical Center of Serbia, Belgrade, Serbia & Montenegro, SUniversity Clinical Center Zvezdara, Department of PuImonology, Belgrade, Serbia &Montenegro W e tested the possible involvement of C F I R mutations and polymotphisms in etiology of disseminated bronchiectasis ( D E ) of u n k n o w n cause, in 19 Serbian patients T h e w h o l e coding region and intr onic boundaries of the CFFR g e n e w e r e analyzed by d e n a t u r i n g gradient g e l electropboresis ( D G G E ) mad subsequent D N A sequencing. In 2/19 patients, two different CFTR mutations w e r e detected. One patient was a compound heterozygote (V920L/R75Q) and one was heterozygous for R75Q. T h e cumulative allelic frequency of mutations was 7.9% (3/38 alleles). IVS8 5T allele was not found ha any of the patients. T h e incidence of the M 4 7 0 allele was 28.9% (11/38 alleles). Several common silent mutations (1716G/A, 2694T/G, 4002A/C~ 4404C/T) and nucleotide changes ha n o n coding regions (875+40A/G, GATT6/7, 1011+11C/T) w e r e identified. Frequency of CFTR mutations obtained ha this study was not significantly higher than in general population and our results do not indicate a maj or role of CFFR g e n e mutations ha the etiology of D B . In spite of the facts that the clinical selection of patients was strict mad that the complete coding region of the CFTR g e n e was screened, d u e to the small sample size, these results should be considered preliminary and need to be confirmed in a larger study. Recent publications by K i n g et al and Casals et al reported controversial results regarding the involvement of CFFR ha development of D B , so further multicentre studies on a larger cobott of clinically w e l l defined patients are needed to resolve these conflicting results.
16 Influence of Interleukin-1O on airways colonizafion by Aspergillus fumigatusin cystic fibrosis patients J. Brouard 1'2, N. ICmaner 1'3, P.Y. Boelle4, H. Corvol 1'5, A. Henrion Caude 1, C. Flamant 1, F. Bremont ~, B. Delaisi7, J.F. D u h a m e l ~, C. M a r guet 8, M. Roussey 9, M.C. Miesch 1, K. Chadelat 1'5, M. B o u l e 1'5, B. Faur oux 1'5, F. Ratjen3, H. Gr asemann 3, A. Clement 1,5
llnserm U719, Armand Trousseau Hospital, Paris, France; ~Departrnent of Paediatrics, Georges Cldme~weau Hospital, Cae~ Fra~we; sChildren's Hospital, University of Essetg Essetg Germany; 4Departrnent of B iostatistic, Inserm U444, StAntoine Hospital, Paris, Fratwe; ~Department of Paediatric Pneumology, Armand Trousseau Hospital, Paris, France; 6Department of Pneumology and GastroenterologN Purpan Children's Hospital, Toulouse, Fratwe; 7Department of Paediatrics, Robert Debrd ChiMren's Hospital, PaAs, France; aDepartment of Paediatrics, Charles NicoIle Hospital, Rouen, Fratwe; ;Department of Paediatrics, South Hospital, Rennes, Fratwe Recent evidence suggests that genetic variants affecting t h e production of interleukin (IL) 10 may play a role in the response to pathogens ha cystic fibrosis (CF). T h e study was designed to seek for an association between alleles carried at position 1 0 8 2 o f t h e l L 10promoter and phenotypical data from 378 patients w i t h CF. After adjusting for potential confounding variables a significant relationship was found between the 1082GGgenotypeandbothAfumigatuscolonizationand allergic bronchopulmonary aspergillosis (ABPA). In addition, higher serum levels of I L 10 w e r e observed ha patients chronically infected w i t h Afurnigatus, and this was associated w i t h a significant increased frequency of 1082G allele. These genetic and functional studies suggest that promoter variants of I L 10 may predispose to develop A fumigatus colonization and A B P A ha CF.